The Genetics of Cancer Presenters Patrick Day Rachael Hanks Leila Shirazi

1. The Genetics of Cancer Presenters Patrick Day Rachael Hanks Leila Shirazi

2. History of Cancer • Cancer has been documented as early as 3000 B.C. • Recorded treatments of cancer since 1600 B.C. • Egyptians would burn or cut off cancerous tumors, also they would mix pig brains and freshly ground dates and insert into the urinary tract for some internal cancers • By 300 B.C Hippocrates had identified several different types of cancer • Cancer effects about 1 out of every 3 people

3. In the 1980’s-1990’s researchers identified parts of the genome that only infected individuals shared, such as chromosomal aberration or a unique DNA sequence. The research continued on specific genes that’s could effect cell cycle control. This led to the discovery of more then 100 oncogenes, and more then 30 tumor suppressing genes. Oncogenes- cause cancer when they are inappropriately activated Tumor suppressing genes- deletion or inactivation of these genes causes cancer. Findings of Cancer

4. Function Of Cancer Genes Discovered Dutch researcher Sebastian Nijman has discovered new genes which are involved in the development of cancer. The results of his research have led to a new treatment for patients with an inherited form of cancer, cylindromatosis. (www.sciencedaily.com) Cylindromatosis- Patientswith the very raregeneticcondition cylindromatosis develop a lot of benign tumours on the skin. These tumours mainly occur on the head where they can cause serious malformations.

5. Cancer cells can divide infinitely if provided enough nutrients and space Cancer cells can produce telomeres Cancer cells look much different then a normal cell Cancer cells can metastasize (Spread) Induce local blood vessel formation Increased mutation rate Normal cells divide until the telomeres on the cell run out Normal cells do not divide as often as cancer cells Cell division is controlled Adhere to the surroundings of the other cells (Takes the same shape as cells around it) Plasma membrane has less fluid compared to a cancer cell Difference Between Cancer cells and Regular cells

6. Diagram of Cancer cells V.S.Normal cells

7. How Cancer cells Form • Cancer cells are formed when a normal cell looses its ability to control it’s division rate • Cancer can form from environmental triggers: Smoking, drinking, stress • Mutations in cells can cause them to become cancerous • Cancer cells squeeze into the blood stream which allow them to travel to other parts of the body • A loss of balance in tissue cells that can divide continually or frequently • Cancer cells could come from stem cells or regular cells that have gone through a series of mutations

8. Dedifferentiation reverses specialization Mutations in a differentiated cell could reactivate latent “stemness” genes, giving the cell greater capacity to divide while causing it to lose some of its specialization. To much repair may trigger tumor formation If the epitheluim is occasionally damaged, resting stem cells can become activated and divide to fill the tissue. If the injury is severe, the present activation of stem cells to renew the tissue can veer out of control, causing an abnormal growth Other Causes of Cancer

9. DNA Microarrays • Some cancer’s look the same as normal cells under a microscope, with the use of DNA microarray analysis, we have been able to refine and even individualize cancer diagnosis and treatment. • The vertical columns of squares represent tumor samples and the horizontal rows compare the activities of particular genes- The red tone indicates higher-then-normal expression and the blue indicates lower-then-normal expression.

10. Germline In germline cancer, every cell has one gene variant that increases the chance of a person getting cancer. This type of predisposition is known as a Mendelian trait. This is a cancer that is passed through generations of people and is hard to avoid Sporadic Sporadic cancer forms when a dominate mutation occurs in a cell, this is caused by environmental triggers such as exposure to radiation or a chemical, can cause the somatic mutations that cause cancer. This cancer is strictly caused by environmental factors and can be avoided Germline V.S. Sporadic Cancer

11. Angiogenesis nurtures a tumor Cells starved for oxygen deep within a tumor secrete vascular endothelial growth factor, which stimulates nearby capillaries to extend branches towards the tumor helping it to grow. Shifting the balance in a tissue towards cells that divide If a mutation renders a differentiated cell able to divide to yield other cells that frequently divide, then over time these cells may take over, forming an abnormal growth Causes of Tumors

12. Cancer Stem cells • A cancer stem cell can divide to self-renew and give rise to a cancer cell, which in turn can also spawn abnormal daughter cells. • Upsetting the balance of stem and progenitor to differentiated cells can cause cancer as excess, fast dividing cells accumulate. • The cancer causing mutations can occur in the cancer stem cell- in this case, the early progenitor cells form the tumor which may also spawn abnormal daughter cells.

13. Genes Associated With Cancer • Oncogenes- (recessive) activate improper cell division which leads to cancer. (proto-oncogenes are normal and control cell cycles.) • Tumor suppressors- (dominant) normally prevent cancer, but can mutate so that part of a gene is missing, thereby eliminating its function and causing cancer. • DNA repair genes- normally repair damaged DNA. Faulty DNA allows mutations to build up and mutant cells to divide. The bright blue enlarged cells are carrying oncogenes.

14. Proto-Oncogenes and Oncogenes • Proto-Oncogenes are active when high cell division rates are necessary (like in wounds). • Oncogenes are point mutations of proto-oncogenes, activated at non-wound sites. • Rapid cell division in undamaged tissue leads to cancerous growths (also known as tumors). A single base change in a proto-oncogene causes bladder cancer. The oncogene RET alters growth factors or growth factor receptors and can lead to Thyroid cancer.

15. Transformations of Gene Expressions • Proto-oncogenes can become oncogenes when placed next to virus-infected cells. • When a chromosome is inverted or translocated, proto-oncogenes can “turn on” and become oncogenes if they are moved near very active genes. • The immune system can contribute to overexpression of oncogenes by producing an excess of antibodies to accommodate oncogenes. Burkitt lymphoma is caused when proto-oncogenes are activated along with antibody genes.

16. Fusion Proteins • When proto-oncogenes are read together as a pair, the result is a double gene product, or a fusion protein. • Fusion proteins can take control of cell division. Rapid cell division can cause cancer. • Fusion proteins are most commonly associated with cancers of the blood, including leukemia. • Pieces of chromosomes that are randomly translocated to others during cell division can lead to fusion proteins, and in turn, to various cancers. Fusion proteins can cause childhood cancers of the blood such as leukemia.

17. Excessive Receptor Signals and Her-2/neu Breast Cancer • 25% of women with breast cancer have 1-2 million copies of an oncogene producer (a protein) called Her-2/neu. Normal women have 20,000-100,000 copies. • These proteins bind to tyrosine kinase receptors which, together, send too many signals to tell cells to divide. • A drug called Herceptin can help by stopping some of the receptors from sending out too many signals for cell division.

18. Tumor Suppressors • A tumor suppressor can mutate into a gene that causes cancer. The mutated gene has usually had some kind of deletion which removes part or some of its normal functions. Wilms’ tumor is the result of a mutated tumor suppressor. In this form of cancer, a child’s kidney cells divide at the same rate as would an embryo’s, forming a tumor.

19. Retinblastoma (RB) • Retinoblastoma or (RB) is a rare childhood eye cancer. • Most RB is the result of a partial deletion on Chromosome 13. • In 1987, researchers found the RB gene and have linked it to other cancers such as breast, lung, and prostate cancer. RB is a childhood eye cancer that results in one or both of the eyes developing an average of three tumors. On the left is a normal cell with no Chromosome 13 deletion. On the right is a cancerous cell with deletion.

20. The “Two-Hit Hypothesis” • Alfred Knudson was one of the first to recognize tumor suppressors and form the “two-hit hypothesis in his observations of RB in children. • Two mutations can lead to RB: - the first mutation is inherited and can affect a newborn with just a single mutation in one somatic eye cell. - the second mutation, in its non-inherited form, appears later in childhood. Alfred Knudson is now widely recognized for his research on RB and the “two-hit” hypothesis.

21. The p53 Gene • p53 is a gene that codes for a protein which decides whether a cell should repair DNA copy errors or die. • Much like the RB gene, if there is a slight mutation or deletion of the p53 gene, a cell with damaged DNA can be allowed to divide, leading to cancer. • More than ½ of all cancers involve some sort of mutation or deletion in the p53 gene. • Environmental triggers such as viruses, radiation, and smoking can lead to mutations in the p53 gene. The p53 gene.

22. BRCA-1 and Breast Cancer • BRCA-1 codes for a protein that is necessary for DNA repair. • Mutations in BRCA-2 (a gene that is very similar to BRCA-1) can cause breast cancer, or lead to other kinds of cancer. • BRCA-1 stands for “breast cancer predisposition gene 1.” • It is a mutated tumor suppressor gene that, when inherited, has a late onset of symptoms for the affected individual. A breast cancer survivor.

23. Series of Genetic Changes • “Gatekeeper” genes control mitosis and apoptosis (cell death). • “Caretaker” genes control the mutation rates of gatekeeper genes. • Series of genetic changes in different stages of cancer can help researchers to pinpoint certain mutations and develop prevention treatments. Understanding genetic changes in the different stages of colon cancer could potentially lead to preventative treatments.

24. Brain Tumors On the left is a normal brain, and the blue mass in the right brain is an astrocytoma. • Astrocytomas are the most common kinds of brain tumors. • They are the result of a series of single-gene and chromosomal changes that occur in different stages of the growth of the tumor.

25. Colon Cancer • Only 5% of colon cancer cases are inherited. • Colon cancer begins with the build-up of tiny colon polyps, which leads to a condition called FAP. Colon lining cells that do not die on schedule build up and lead to cancer. • Researchers have pinpointed the direct cause of colon cancer to be linked to a deletion in Chromosome 5. • A kind of chain reaction in this mutation leads to others that can spread the cancer (p53, PRL-3, and TGF).

26. EnvironmentalFactors • Mutating genes that help the cancer cells and that strongly affect the person. This can happen in virtually anyone.

27. Carcinogens Carcinogens are any substance, illness or exposure circumstances that directly raises the risk of cancer. There is a four-grouped classifying system, one-four of how carcinogenic things are to humans. However many studies only prove correlations instead of cause and effect.

28. Lowering Your Risk Avoid certain high-risk factors Chemoprevention • Taking certain nutrients, plant extracts, or drugs, which include folic acids, vitamin D, extracts from green tea and tomatoes, and more.

29. Methods to Study Cancer-Environment Links Population Study • Population disease incidence in different groups of people. Yet too many variables make it hard to establish solid cause & effects.

30. Case-Control Study People with a certain type of cancer are matched along with people much like them (weight, age, ethnicity, etc.) but who are healthy. Researchers then look at significant differences between the two’s lifestyle and history. Prospective Study A study that follows two or more groups as they comply to a specified activity plan. They are continuously checked on for cancer. However some forms of cancer may take several years to appear.

31. Diagnosis and Treatments After a screening test (blood or x-rays), symptoms occurring, or patient feels it, there are several options in which the person can take for treatment.

32. Surgery • Simply remove the tumor, however if even one cancer cell is left though, a tumor will return. Radiation & Chemotherapy • Kills all cells that divide rapidly. This also kills healthy cells. Newer Types of Treatment • Include inhibiting telomeres, blocking hormone receptors, and drawing the blood out of the cancer cells. Alternative Methods • Prayers, herbs, etc.

33. Genomic Approaches Breast cancer is a great example of how genes are helping us understand and fix the problem. Phenotype and Genotypes are taken into consideration • Depending on the women, the breast cancer either has receptors for estrogen or progesterone. That will determine what medicine and recovering therapy she will receive.

34. Cancer diagnosis will continue to be based more heavily on DNA microarrays, which will look at gene expression and genotype. • This will be able to give patients immediate treatments that fit their type of cancer. Also predicts side affects that particular patient will get.

35. References Function of Cancer Genes Discovered, Science Daily, May 13, 2005 March7,2007,http://www.sciencedaily.com/releases/2005/05/50513224031.htm Lewis, Ricki, Human Genetics, New York: McGraw-Hill, 2005 The p53 tumor suppressor gene. National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov. Jan 10 2007. Wikipedia, March 5, 2007, Free Encyclopedia, March 6, 2007, <http://en.wikipedia.org/wiki/Cancer>

36. Bonus Question! Q: What are the most common type of brain tumors?

37. A: Astrocytomas